title: Hypoxia-induced regulation of the very low density lipoprotein receptor.
abstract: The very low density lipoprotein receptor (VLDLr) is highly upregulated during hypoxia in mouse cardiomyocytes and in human and mouse ischemic hearts causing a detrimental lipid accumulation. To know how the gene is regulated is important for future studies. In this study, we have thoroughly mapped the 5'-flanking region of the mouse VLDLr promoter and show that the hypoxia-mediated increase in VLDLr expression is dependent on Hif-1α binding to a hypoxia responsive element (HRE) located at -162 to -158bp 5'of translation start. We show that classical HRE sites and the previously described PPARγ and Sp1 binding are not involved in the hypoxia-induced regulation of the VLDLr promoter. Using a chromatin immunoprecipitation (ChIP) assay, we show that Hif-1α specifically binds and activates the mouse VLDLr promoter at the previously described non-classical HRE in HL-1 cells. We also show that the same HRE is present and active in response to hypoxia in human cardiomyocytes, however at a different location (-812bp from translation start). These results conclude that in the hypoxic hearts of mice and men, the VLDLr gene is regulated by a direct binding of Hif-1α to the VLDLr promoter.
authors.affiliation: Department of Molecular and Clinical Medicine, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden. jeanna.perman@wlab.gu.se
authors.forename: Jeanna Perman
authors.initials: JP
authors.lastname: Sundelin
authors.forename: Ulf
authors.initials: U
authors.lastname: Lidberg
authors.forename: Ali Moussavi
authors.initials: AM
authors.lastname: Nik
authors.forename: Peter
authors.initials: P
authors.lastname: Carlsson
authors.forename: Jan
authors.initials: J
authors.lastname: Borén
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D017931:DNA Primers; D000860:Hypoxia / Q000503:physiopathology*; D051379:Mice; D047495:PPAR gamma / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011973:Receptors, LDL / Q000235:genetics / Q000502:physiology*; D016329:Sp1 Transcription Factor / Q000378:metabolism
chemical_list: D017931:DNA Primers; D047495:PPAR gamma; D011973:Receptors, LDL; D016329:Sp1 Transcription Factor; C036053:VLDL receptor
keywords: Hypoxia inducible factor 1 alpha; Hypoxia responsive element; Very low density lipoprotein receptor